Catalyst

Acid-base catalytic reaction

Catalysts
Catalysts increase the rate of a reaction
by decreasing the activation energy of
the reaction.
Catalysts change the mechanism by
which the process occurs.

Catalysts
One way a
catalyst can
speed up a
reaction is by
holding the
reactants
together and
helping bonds
to break.

Enzymes

Enzymes are
catalysts in
biological
systems.
The substrate fits
into the active
site of the
enzyme much like
a key fits into a
lock.

Influence of pH on reaction rate

The hydrolysis of esters is catalysed by both acid and base:

H3C

O CH 3
O

H3C

H2O

O CH 3

H2O

OH
H3C
OCH 3
OH2

H3C

OH
H3C
OCH 3
O
H
OH

O
OCH 3
OH H
O

H3C

log kobs

OH

7.0

pH

OH

+ CH3O

acid catalysed
hydrolysis

base catalysed
hydrolysis

Another example: imine formation:

R NH 2 + H+

inactive

C O + H+

C OH
active

R NH 2 +

C OH

H2
R N C OH

log kobs

nucleophile

R NH 3+

4.5
pH

N C
R

HN C
R

H
R N C OH2

pH optimum ~ 4.5

Slope of plot of log kobs vs. pH is often close to 1:

linearly dependent on [H+] or [OH-]

Two mechanisms for acid catalysis

Specific acid catalysis:
- A proton is transferred to the substrate in a rapid preequilibrium;
subsequently, the protonated substrate reacts further to the
product(s) in the rate determining step:
fast

S + HA
SH+

slow

SH+ + A
products

General acid catalysis:

- Proton transfer occurs in a slow, rate determining step;
subsequently, the protonated substrate rapidly reacts to give the
product(s):
S + HA
SH+

slow
fast

SH+ + A
products

Specific acid/base catalysis

Usually found for electronegative elements (O, N), where proton
transfer is fast:
K

E + HA

EH+ + A

fast

The second step is rate determining and can be mono- or

bimolecular:
k1

EH+

H2O

products

or EH+ + H2O

k2

products

Reaction rate:

[E][HA]
= k1[EH ] = k1K
[A - ]
+

we can now write:

since

slow

(A1 mechanism)

slow

(A2 mechanism)

[H 3O + ][A - ]
Ka =
[HA]

k1K
=
[E][H 3O + ] = k'[E][H 3O + ]
Ka

So the rate is only dependent on the pH, not on [HA] !!

Specific base catalysis

Example: the retro-aldol reaction of I:

x
x

OH
CH 3
CH 3

H3C
I

base

O
2

H3C

CH 3

kobs

x
x
x

[OH-]

kobs is directly proportional to [OH-]. Addition of more base

(in buffer) at constant pH has no effect on kobs;
[OH-] is the only base that occurs in the rate equation.

General acid/base catalysis

Proton transfer is the rate determining step.
Example: the hydrolysis of ortho esters:

H3C

OC2H5
OC2H5 + H2O
OC2H5

H+

O
H3C

OC2H5

+ 2 C2H5OH

III

The reaction is studied in a series

of buffers (m-NO2-Ph-OH/m-NO2Ph-O): reaction rate increases

with increasing buffer

concentration, even if the pH
remains constant

k(buffer)

{k(H3O+)[H3O+] + k(H2O)[H2O]}[III]
[buffer]

= {k(H2O)[H2O] + k(H3O+)[H3O+] + k(m-NO2-Ph-OH)[m-NO2-Ph-OH]}[II

NUCLEOPHILICITY
WHAT IS A NUCLEOPHILE ? A BASE ?
WHAT MAKES A GOOD NUCLEOPHILE?

NUCLEOPHILES AND BASES

THE FUNDAMENTAL DISTINCTION

Nucleophilicity

Basicity

kinetic (or rate) parameter

thermodynamic (or equilibrium)

parameter.

All nucleophiles are bases ...

and all bases are nucleophiles.
A good base is not necessarily
HOWEVER : a good nucleophile, and vice versa.

NUCLEOPHILE VERSUS BASE

Nu1
Nucleophilicity = Kinetic
Rate = k2[RX][Nu]

Nu2 is a better
nucleophile
( FASTER RATE )
Nu2

good nucleophile
increases k2
(I.e., the rate)

Basicity = Thermodynamic
B:

B-H

+ H+
strong base
shifts equilib.

Nu1 is a
better base
( STRONGER BOND )

DIFFERENT PLACES ON THE ENERGY PROFILE

DETERMINE NUCLEOPHILICITY AND BASICITY
NUCLEOPHILES
Nucleophilicity is
determined here
activation energy
and rate (kinetics)
faster is better
BASES
Basicity is
determined here
strength of bonds
and position of
equilibrium
lower energy is better

IS THE NUCLEOPHILE IMPORTANT

IN BOTH SN1 AND SN2 REACTIONS ?

NUCLEOPHILES
IMPORTANCE IN SN1 AND SN2 REACTIONS
Nucleophiles are unimportant in an SN1 reaction;
they are not involved in the rate-determining step.

SN1 rate = K1 [RX]

The nature of a nucleophile is only important to
an SN2 reaction.

SN2 rate = K2 [RX][Nu]

WHAT IS A
GOOD NUCLEOPHILE ?
SN2 REACTIONS

WHAT IS THE IDEAL NUCLEOPHILE ?

LARGE

..
: ..
Y:

SN2 REACTIONS

STERIC PROBLEMS
no way ! bad

R
SMALL

.. :..
X:

good

: Br

R
Smaller
is better !

R
For an SN2 reaction the nucleophile must find
the back lobe of the sp3 hybrid orbital that the
leaving group is bonded to.

EXPECTED IDEAL NUCLEOPHILES

cyanide

ROD OR SPEAR -:C

N:
+
SHAPED
:N
N
N:
azide

These types
should be
able to find
the target !

SMALL
SPHERES

.. - .. :F:
:Cl:
..
..

Generally this idea is correct.

etc.

OUR NAVE EXPECTATION

We would expect the halides to be good nucleophiles:
ionic radii:
1.36 A

1.81 A

F-

Cl-

1.95 A

2.16 A

smallest
ion

Br -

I-

and we would expect the smallest one (fluoride)

to be the best nucleophile,
.. however, that is not usually the case.

EXPERIMENTAL RESULTS

RELATIVE RATES OF REACTION FOR THE HALIDES

CH3-I + NaX

MeOH

CH3-X + NaI

Rate = k [CH3I] [X-]

k
-

5 x 102

2.3 x 104

6 x 105

Cl

Br
-

2 x 107

slowest

fastest

* MeOH solvates like water but dissolves everything better.

SN2

SOLVATION
Solvation reverses our ideas of size.

HEAT OF SOLVATION
ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER

F-

gas phase

- 120 Kcal / mole

HEAT OF SOLVATION
F- (g)

F-

H
H
O

O
H

SOLVATED
ION

H
O
water solution

F- (aq)
The interaction between
the ion and the solvent
is a type of weak bond.
Energy is released when
it occurs.
Solvation lowers the
potential energy of the
nucleophile making it
less reactive.

IONIC
RADIUS 1.36 A
smallest
ion

HALIDE IONS

Heats of
solvation
in H2O

- 120

1.81 A

1.95 A

Cl

Br -

- 90

- 75

2.16 A

I-

- 65

Kcal / mole

X(H2O)n

increasing solvation
larger n

smaller n

SMALL IONS SOLVATE MORE THAN LARGE IONS

H O

CH3CH2 O

CH3 O

H
WATERHAS

H
+

H O

H+
polar OH bonds

R N

H
SOLVENT

H
O H

O
+

H O
H

O
H

H O
-

O
H

H
H

H O

Water is a polar molecule.

Negative on the oxygen end, and positive on the hydrogen end.
It can solvate both cations and anions.

SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES

strong interaction
with the solvent

O H
H H O
H
H
H O
O
H
H
H H
H O H
O
O
H
H

BETTER
NUCLEOPHILE

H O

H
O
H
solvent
shell

Effective size is larger.

Heavy solvation lowers the
potential energy of the nucleophile.
It is difficult for the solvated nucleophile
to escape the solvent shell.
This ion is less reactive.

H O

H
H

...smaller
solvent shell
...escapes
easily
more
potential
energy

weak interaction
with the solvent

PROTIC SOLVENTS
H O
H
water

CH3CH2 O

CH3 O

H
methanol

R N

ethanol

H
H

amines

H
H
H O
Water
is
an
example
of
a
protic
solvent.
O
H
O
+ H
H
H
H O
+
X
Mthat have
H O
Protic solvents are those
O
H
H
+
H N-H
H O
O-H,
or S-H
bonds.
H O
H
H
Protic solvents can form hydrogen bonds and can
solvate both cations and anions.

LARGER IONS ARE BETTER NUCLEOPHILES

IN PROTIC SOLVENTS
THREE FACTORS ARE INVOLVED :

2
3

In protic solvents the larger ions are solvated less

(smaller solvent shell) and they are, therefore,
effectively smaller in size and have more potential
energy.

Since the solvent shell is smaller in a larger ion

it can more easily escape from the surrounding
solvent molecules during reaction. There is more
potential energy.

The larger ions are thought (by some) to be

more polarizable.
see the next slide ..

POLARIZABILITY
Polarizability assumes larger ions are able to easily
distort the electons in their valence shell, and that
smaller ions cannot.

Br
VERY
HYPOTHETICAL

The distortion of large ions is easier because the

orbital clouds are more diffuse.
The nucleophile flows into the reactive site.

BASICITY
If everything else is equal, the stronger base is
the better nucleophile.
This principle shows up in a period, where
atoms do not vary appreciably in size, and
solvate to similar extents.

OH- is a better nucleophile than F-

NUCLEOPHILICITY TRENDS
IN PROTIC SOLVENTS

OBSERVED NUCLEOPHILICITY TRENDS

H2O OR OTHER PROTIC SOLVENTS
GROUP IV

VI

VII

increasing nucleophilicity (ROWS)

CH3-

basicity

NH2-

OH-

F-

PH2-

SH-

Cl-

increasing
nucleophilicity
(COLUMNS)

BrImore solvation,
larger effective size,
lower potential energy

basicity

RELATIVE RATES OF SOME NUCLEOPHILES

MeOH

CH3-I + Nu:
CH3-Nu + IRate = k [CH3I] [X-]
F5 x 10
CH3COO2 x 104
Cl2.3 x 102
2

C6H5ON3BrCH3OCNIC6H5S-

6x
6x
5x
2x

5.6 x 105
105
105
2 x 106
106
107
8 x 109

CHARGED

CH3OH

SN2
1.0 (solvolysis is faster)

NH3
3.2 x 105
(CH3)2S 3.5 x 105
C6H5NH2
5 x 105
C6H5SH 5 x 105
these are the good
nucleophiles, but
watch out, some
are strong bases

NEUTRAL

APROTIC SOLVENTS

APROTIC SOLVENTS

O
CH3

O
CH3

dimethylsulfoxide
DMSO

H C N CH3
CH3
dimethylformamide
DMF

O
CH3

C CH3

acetone
if scrupulously
free of water

H3C
H3C

O
N

H3C

CH3
CH3

CH3

hexamethylphosphoramide
HMPA

CH3 C N
acetonitrile

APROTIC SOLVENTS
DO NOT HAVE
OH, NH, OR SH BONDS
They do not form
hydrogen bonds.

APROTIC SOLVENTS SOLVATE CATIONS,

BUT NOT ANIONS (NUCLEOPHILES)

H3C

H3C
S
H3C

S + CH3
-

O M+ O
O

CH3

S CH
3

crowded

CH3
S

CH3

XThe nucleophile is
free (unsolvated),
and therefore is small
and not hindered by
a solvent shell.

DIMETHYLSUFOXIDE
space-filling

O
S

density - electrostatic potential plot

DIMETHYLFORMAMIDE

CH3
H3C N C H
+

H C N CH3
CH3

nucleophile is free
(unsolvated)

OBSERVED NUCLEOPHILICITY
APROTIC SOLVENTS
GROUP IV

VI

VII

increasing nucleophilicity (ROWS)

CH3-

NH2-

OH-

F-

PH2-

SH-

Cl-

increasing
nucleophilicity
(COLUMNS)

BrIdecreasing
ionic size
The direction of the red arrow (COLUMNS) represents a
different order than in protic solvents.

basicity

WHY NOT ALWAYS USE

APROTIC SOLVENTS FOR SN2 ?
Mostly, it is a matter of expense.
Water, ethanol, methanol and acetone are much
cheaper, especially water.

Water
free
Methanol $14.70 / L
Ethanol $15.35 / L
Acetone $16.60 / L

DMSO
DMF
HMPA

$47.50 / L
$33.75 / L
$163.40 / L

Cheapest grades available, Aldrich Chemical Co., 2000.

SOLVENTS
WHAT ARE GOOD SOLVENTS FOR SN1 AND SN2 ?

SN1 SOLVENTS = POLAR

SN1 reactions prefer polar-protic solvents that
can solvate the anion and cation formed in the
rate-determining step.
ions

R-X

rate-determining
step

R+ +

X-

solvation of both ions

speeds the ionization

Carbocation

SN2 SOLVENTS = NONPOLAR

OR POLAR-APROTIC
SN2 reactions prefer non-polar solvents, or
polar-aprotic solvents that do not solvate the
nucleophile.

..
:..
X:

R
C

SMALL,
UNSOLVATED

R
smaller is better !

: Br

CF 3COOH

POLAR
APROTIC
SOLVENTS

CH3

O+
S CH3

H2O
CF 3CH2OH

SN1

HCOOH
CH3OH

O
H C N CH3
CH3
O
CH3 C CH3

SN2

POLAR

CH3CH2 O CH2CH3
CCl4

CH3CH2OH
CH3COOH

overall
polarity

POLAR
PROTIC
SOLVENTS

CH3CH2CH2CH2CH3

NONPOLAR
SOLVENTS

NONPOLAR

SOLVENT MIXTURES

SOLVENT MIXTURES ARE VERY COMMON

RX

Alkyl halides dont dissolve in water,

but dissolve in most organic solvents.

NaX

Nucleophile salts dont dissolve in most

organic solvents, but dissolve in water.

Both dissolve in a mixed solvent.

miscible solvents

CH3CH2CH2CH2 Cl + NaBr
soluble in EtOH

soluble in H2O

50% EtOH
50% H2O

EXCEPTIONS

NaX

Dissolve in polar-aprotic organic solvents:

DMF, DMSO, HMPA.
NaI and NaCN dissolve in acetone,
but NaCl and NaBr do not

THE BOTTOM LINE

SN1
CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY
The nucleophile is not involved in the rate-determining step.

SN2
BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT
The nucleophile is involved in the rate-determining step.

Hard-Soft Acid-Base
Theory

Definitions
Arrhenius acids form hydronium
ions in water, and bases form
hydroxide ions. This definition
assumes that water is the solvent.
Brnsted and Lowry expanded
upon the Arrhenius definitions, and
defined acids as proton donors and
bases as proton acceptors. They also
introduced the concept of conjugate
acid-base pairs.

Lewis Acids & Bases

The Lewis definition further
expands the definitions. A base is an
electron-pair donor, and an acid is an
electron-pair acceptor. The two
combine to form an adduct.
A + :B A-B

Lewis Acids & Bases

This definition includes the
standard Brnsted-Lowry acid-base
reactions:
H+(aq) + :NH3(aq) NH4+(aq)
It also includes the reactions of
metal ions or atoms with ligands to
form coordination compounds:
Ag+(aq) + 2 :NH3(aq) Ag(NH3)2+(aq)

Lewis Acids & Bases

In addition, electron-deficient
compounds such as trivalent boron is
categorized as a Lewis acid.
B(CH3)3 + :NH3 (CH3)3BNH3
The HOMO on the Lewis base
interacts with the electron pair in the
LUMO of the Lewis acid. The MOs of
the adduct are lower in energy.

Lewis Acids & Bases

The LUMO and HOMO are called frontier

orbitals. If there is a net lowering of energy,
the adduct is stable.

BF3 + NH3
The LUMO of the acid, the HOMO of
the base and the adduct are shown
below:

Lewis Acids & Bases

There is the possibility of
competing reaction pathways
depending upon which reactants are
present, and the relative energies of
possible products. As a result, a
compound such as water may serve
as an acid, a base, an oxidizing agent
(with Group IA and IIA metals) or a
reducing agent (with F2).

Lewis Acids & Bases

A Lewis base has an electron pair
in its highest occupied molecular
orbital (HOMO) of suitable symmetry
to interact with the LUMO of the
Lewis acid. The closer the two
orbitals are in energy, the stronger
the bond in the adduct.

Hard and Soft Acids and

Bases
The polarizability of an acid or
base plays a role in its reactivity.
Hard acids and bases are small,
compact, and non-polarizable.
Soft acids and bases are larger,
with a more diffuse distribution of
electrons.

Hard and Soft Acids and

Bases
In addition to their intrinsic
strength,
Hard acids react preferentially with
hard bases, and soft acids react
preferentially with soft bases.

Hard and Soft Acids & Bases

There have been many attempts to
categorize various metal ions and
anions to predict reactivity, solubility,
etc.
R.G. Pearson (1963) categorized
acids and bases as either hard or soft
(using Kf values).
Hard acids bond in the order: F->Cl>Br->I-

Hard and Soft Acids & Bases

Hard acids tend to bind to hard bases.
Soft acids tend to bind to soft bases.

Charge Density Hard Acids

Hard acids typically have a high
charge density. They are often metal
ions with a (higher) positive charge
and small ionic size. Their d orbitals
are often unavailable to engage in
bonding.

Charge Density Soft Acids

Soft acids typically have lower
charge density (lower ionic charge
and greater ionic size). Their d
orbitals are available for bonding.
Soft acids are often 2nd and 3rd row
transition metals with a +1 or +2
charge, and filled or nearly filled d
orbitals.

Acid or Base Strength

It is important to realize that
hard/soft considerations have
nothing to do with acid or base
strength. An acid or a base may be
hard or soft and also be either weak
or strong.
In a competition reaction between
two bases for the same acid, you
must consider both the relative
strength of the bases, and the

D. Energetics of Nucleophile-Electrophile Interactions

qn qe
2( c n ce)2
E

r
E HOM O E LUM O
qn and qe are charges on nucleophile and electrophile, respectively.
cn and ce are orbital coefficients of nucleophile HOMO and electrophile
LUMO, respectively.
is the resonance integral.
EHOMO = energy of nucleophile HOMO
ELUMO = energy of electrophile LUMO
Electrostatic term: important for interactions of hard acids with hard bases
Orbital interaction term: important for interactions of soft acids with soft bases
65

Bases (nucleophiles)
Type

Hard

Intermediate

Soft

Species

Examples

small halide anions

F-, Cl-

oxygen nucleophiles

H2O, ROH, HO-, RO-,

ROR, MeCO2-, SO42-,
PO43-

amine nucleophiles

RNH2, H2NNH2

larger halide anions

Br-

nitrogen nucleophiles

C6H5NH2, C5H5N, N3-

oxygen nucleophiles

NO2-, SO32-

sulfur nucleophiles

RSR, RSH, RS-

phosphorus
nucleophiles

R3P, (RO)3P, R3As

carbon nucleophiles

CN-, CO, R-, C2H4, Ar

others

H -, I -

66

Acids (electrophiles)
Type

Hard

Intermediate

Soft

Species

Examples

high charge/radius
cations

H+, Li+, Mg2+, Ca2+, Al3+,

Cr3+, Ti4+, I5+

group II species

Be(CH3)2

group III species

Al(CH3)3, BF3, B(OR)3

H-bond donors

ROH, HOH, RNH2, RNH3+

moderate charge/radius
cations

Fe2+, Cu2+, Zn2+, Pb2+, Sn2+,

Co2+, Ni2+

carbocations

(CH3)3C+, ArH+

low charge/radius
cations

Cu+, Ag+, Au+, Hg+, Hg2+,

I+, Br+, RO+

carbon electrophiles

RL, ArL (L = nucleofuge)

diatomic halogens

I2, Br2, ICN

radicals

O, Cl, Br, I, RO
67